Neuroendocrine tumors of the pancreas are relatively rare but there remains considerable interest in these entities because of the complexity of the tumor spectrum and the uncertain histogenesis. Unfortunately, animal models that can faithfully replicate human disease and enable a more thorough investigation of the etiology of the disease process are few. We have created what appears to be a remarkably useful new animal model for pancreatic islet cell carcinoma as a result of cell-specifically deleting floxed Rb and p53 loc within the renin- expressing cell compartment of pancreas. The predominant neoplasia observed is an islet cell carcinoma, expressing glucagon, which arises with high penetrance and exhibits symptoms and profound metastatic spread to sites representative of the human disease, resulting in death by 5-6 months. In the human disease the primary metastatic sites are regional lymph nodes and liver, which is mimicked by our model. This model exhibits unique features which will allow us to foster better understanding of pancreatic islet cell development, the role the renin-angiotensin system therein, islet cell carcinogenesis, and the associated metastatic process, with the aim of ultimately identifying genetic signatures for these processes. We hypothesize that renin is transiently expressed in early glucagon lineage differentiation and that the loss of p53 and Rb predisposes these islet cells to frank carcinogenesis upon the occurrence of stochastic co-operating genetic and epigenetic abnormalities. Furthermore, we propose that additional or specific genomic insults are required for the cells to acquire a metastatic phenotype. Our hypothesis is supported by our preliminary findings that the renin expressing cells co-localize with the alpha islet cells expressing glucagon and that both primary and metastatic tumors, stochastically arising, continue to express glucagon. This is further supported by recent literature demonstrating that human pancreatic progenitor cells exhibit highly regulated expression of various components of the renin-angiotensin system throughout the progenitor cell differentiation to various islet cell types. The current proposal will use Next Generation Sequencing of the exome, all transcripts, and of the methylome to identify co-operating mutations, gene expression changes and DNA methylation changes occurring within lineal descendants of the Rb-, p53-, renin-expressing cells of normal pancreatic islets that are associated with the stochastically arising primary tumors and corresponding liver metastases. Furthermore, the ability to use fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease pathology. We further expect that the Confetti reporter will assist in the identification o clonal expansion of individual colored cells in the islet for each primary tumor, and facilitate correctly pairing the colored metastatic tumor with the same colored primary tumor. This will increase the power of the pairwise comparisons between primary and metastatic tumors and will ultimately allow for dissection of multiple molecular routes of metastatic spread.